CN111803715B

CN111803715B - Degradable artificial bone particle with core-shell structure and preparation method thereof

Info

Publication number: CN111803715B
Application number: CN202010693756.4A
Authority: CN
Inventors: 杨晓; 杨龙; 朱向东; 张兴栋
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2020-07-17
Filing date: 2020-07-17
Publication date: 2021-09-07
Anticipated expiration: 2040-07-17
Also published as: CN111803715A

Abstract

The present disclosure describes a degradable artificial bone particle having a core-shell structure, which is characterized in that the degradable artificial bone particle has a core-shell structure, the core-shell structure includes an inner core layer and an outer shell layer coated on the outer surface of the inner core layer, the material of the inner core layer is different from that of the outer shell layer, and the inner core layer and the outer shell layer are in a ceramic phase, the degradation rate of the inner core layer is less than that of the outer shell layer, the outer shell layer is a porous structure, the porous structure includes a plurality of through holes having a first pore size and a plurality of micropores having a second pore size, each pore of the plurality of through holes is communicated with each other, the inner core layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate, and the layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate. According to the present disclosure, artificial bone particles satisfying requirements for ceramic osteogenic properties, angiogenesis properties and degradation properties can be obtained.

Description

Degradable artificial bone particle with core-shell structure and preparation method thereof

Technical Field

The disclosure generally relates to the field of clinical bone repair, and particularly relates to degradable artificial bone particles with a core-shell structure and a preparation method thereof.

Background

Bone defects are one of the common diseases in clinic, and bone tissue defects are caused by various factors such as trauma, inflammation, bone diseases, operation and the like. At present, various methods for treating bone defects include autologous bone grafting, allogeneic bone grafting and the like. Although autologous bone grafting is the gold standard for clinical bone defect repair, it has limited bone supply, difficult shaping and fails to meet the repair requirements of large area and specific shape. Although the allogeneic bone can solve the problem of limited bone source, the allogeneic bone is easy to absorb and deform after being implanted, has strong antigenicity and influences the treatment effect.

In order to solve the above problems, synthetic bone repair materials have been produced, and research and development and industrialization of synthetic bone repair materials are in a new stage of vigorous development driven by huge clinical demands. Currently, active artificial bone filling and repairing materials are generally composed of porous calcium phosphate ceramics. The active artificial bone filling and repairing material has the characteristics of good biocompatibility, degradability and easiness in forming. Porous calcium phosphate ceramics are typically fabricated as massive, wedge, cylindrical, spherical particles. Among them, porous calcium phosphate ceramic spherical particles are widely used clinically.

Currently, calcium phosphate ceramics are generally classified into three types: hydroxyapatite (HA) phase component ceramics, beta-tricalcium phosphate (beta-TCP) phase component ceramics and Biphase Calcium Phosphate (BCP) ceramics formed by compounding the former two phases. The biological activities of these three phase components differ: the HA ceramic HAs good bone conduction capability, but the degradation rate is slow; beta-TCP has high angiogenesis promoting activity, but degrades too fast; the BCP ceramic HAs moderate degradation, is matched with the new osteogenesis speed, HAs the bone conduction capability lower than HA but higher than beta-TCP, and HAs the angiogenesis promoting capability higher than HA but lower than beta-TCP. The requirements of different host bone environments on the osteogenic property, the vascular property and the degradation property of the ceramic are different, and the existing calcium phosphate ceramic is difficult to have various properties.

Disclosure of Invention

The present disclosure has been made in view of the above circumstances, and an object thereof is to provide a degradable artificial bone particle having a core-shell structure, which can satisfy requirements for ceramic osteogenic properties, vascular properties, and degradability, and a method for producing the same.

To this end, the disclosure provides, in a first aspect, a degradable artificial bone particle having a core-shell structure, it is characterized by having a core-shell structure, wherein the core-shell structure comprises an inner core layer and an outer shell layer coated on the outer surface of the inner core layer, the material of the inner core layer is different from that of the outer shell layer, and the inner core layer and the outer shell layer are in a ceramic phase, the degradation rate of the inner core layer is less than the degradation rate of the outer shell layer, the outer shell layer is a porous structure including a plurality of through holes having a first pore size and a plurality of micro holes having a second pore size, the through holes are communicated with each other, the inner core layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphase calcium phosphate, the outer shell layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphase calcium phosphate. In the disclosure, the degradable artificial bone particles with the core-shell structure comprise an inner core layer and an outer shell layer coated on the outer surface of the inner core layer, the inner core layer and the outer shell layer are made of different materials, the inner core layer and the outer shell layer are in a ceramic phase, the degradation rate of the inner core layer is smaller than that of the outer shell layer, the outer shell layer is of a porous structure, the porous structure comprises a plurality of through holes with a first aperture and a plurality of micropores with a second aperture, all the holes of the through holes are communicated with each other, the inner core layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate, and the outer shell layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate. In this case, the artificial bone particles having good ceramic osteogenic property, vascular property and degradation property can be obtained based on actual needs.

In the degradable artificial bone particle according to the first aspect of the present disclosure, optionally, the core-shell structure further includes a single-layer wrapping layer disposed on an outer surface of the outer shell layer, the single-layer wrapping layer is selected from one of hydroxyapatite, β -tricalcium phosphate, and biphasic calcium phosphate, and a material of the outer shell layer is different from a material of the single-layer wrapping layer. In this case, a degradable artificial bone particle having a three-layer structure can be obtained.

In the degradable artificial bone particle according to the first aspect of the present disclosure, optionally, the core-shell structure further includes a plurality of wrapping layers disposed on the outer surface of the outer shell layer, each of the wrapping layers is selected from one of hydroxyapatite, β -tricalcium phosphate and biphasic calcium phosphate, the material of the outer shell layer is different from that of the wrapping layer disposed directly on the outer surface of the outer shell layer, and the material of the adjacent wrapping layers in the plurality of wrapping layers is different. In this case, a degradable artificial bone particle having a multilayered structure can be obtained.

In the degradable artificial bone particle according to the first aspect of the present disclosure, optionally, the first pore size is larger than the second pore size, the first pore size is 30 μm to 400 μm, and the second pore size is 0.1 μm to 2 μm. In this case, adhesion, spreading, crawling and proliferation of osteoblasts on the artificial bone particles can be facilitated.

The second aspect of the present disclosure provides a method for preparing degradable artificial bone particles, which includes: preparing and mixing first calcium phosphate powder, an alginate solution and a binder, adding a foaming agent and water, stirring to obtain first slurry, and heating the first slurry to obtain first foaming slurry, wherein the first calcium phosphate powder is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate; preparing and mixing a second calcium phosphate powder, an alginate solution and a binder, adding a foaming agent and water, stirring to obtain a second slurry, and heating the second slurry to obtain a second foaming slurry, wherein the second calcium phosphate powder is at least one selected from hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate, and is different from the first calcium phosphate powder; extruding and molding the first foaming slurry and the second foaming slurry to form a mixed spheroid of the second foaming slurry and the first foaming slurry, and curing to form a ceramic blank, wherein in the extrusion molding process, the extrusion rate of the first foaming slurry and the extrusion rate of the second foaming slurry are respectively changed in a sine wave form; and sintering the ceramic green body to obtain the artificial bone particles.

In the present disclosure, a first slurry is obtained using a first calcium phosphate powder, an alginate solution, a binder, a foaming agent, and water, the first slurry is heated to obtain a first foamed slurry, a second slurry is obtained using a second calcium phosphate powder, an alginate solution, a binder, a foaming agent, and water, the second slurry is heated to obtain a second foamed slurry, the first calcium phosphate powder and the second calcium phosphate powder are respectively selected from at least one of hydroxyapatite, β -tricalcium phosphate, and biphasic calcium phosphate, and the second calcium phosphate powder is different from the first calcium phosphate powder. In this case, the first and second foaming pastes have through pores by generating bubbles through decomposition of the foaming agent by heating. Extruding and molding the first foaming slurry and the second foaming slurry to form a mixed spheroid of the second foaming slurry and the first foaming slurry, and curing to form a ceramic blank, wherein in the extrusion molding process, the extrusion rate of the first foaming slurry and the extrusion rate of the second foaming slurry are respectively changed in a sine wave form; in this case, the mixed spheroids can be automatically and continuously obtained to form the ceramic green body of the core-shell structure. And sintering the ceramic blank to obtain the artificial bone particles. In this case, the ceramic green body is sintered to obtain artificial bone particles, and in this case, alginate is decomposed and detached during the sintering process to leave abundant micropores inside the artificial bone particles.

In the preparation method according to the second aspect of the present disclosure, optionally, in the sintering treatment, the high-temperature sintering is performed at 1100 ℃ for 2 hours at a heating rate of 3-5 ℃/min, and then the temperature is naturally reduced to room temperature. In this case, the alginate can be decomposed and separated by a specific sintering process so that abundant micropores are left inside the artificial bone particles.

In the preparation method related to the second aspect of the present disclosure, optionally, in the extrusion molding, a first foaming slurry and a second foaming material are respectively extruded by using a coaxial double-layer nozzle, and a ratio of an extrusion rate of the first foaming slurry to an extrusion rate of the second foaming material is 1:3, the phase difference of the sine wave of the extrusion rate of the second foaming slurry to the sine wave of the extrusion rate of the first foaming slurry is 45-90 degrees. In this case, the extrusion rates of the first and second foaming pastes can be matched to automatically and continuously produce mixed spheroids of core-shell structure.

In the preparation method according to the second aspect of the present disclosure, optionally, the size of the artificial bone particles is obtained by adjusting the concentration of the alginate solution and the diameter of the coaxial bilayer nozzle. In this case, artificial bone particles of different sizes can be acquired based on the application scenario.

In the preparation method according to the second aspect of the present disclosure, optionally, during the process of solidifying the mixed spheroid, the mixed spheroid is added into a calcium chloride solution, and calcium chloride in the calcium chloride solution and alginate in the mixed spheroid are cross-linked to form a ceramic green body. In this case, the mixed spheroids can be cured to form a core-shell structured ceramic green body.

In the preparation method related to the second aspect of the present disclosure, optionally, the alginate solution is a sodium alginate solution, the binder is one of methylcellulose, a polyvinyl alcohol solution, a polyethylene glycol solution, a gelatin solution, and a triethanol gel solution, and the foaming agent is a hydrogen peroxide solution. Under the condition, the degradable artificial bone particles with rich micropores can be obtained by utilizing the sodium alginate, and the hydrogen peroxide is decomposed by heating to generate bubbles so as to obtain the first foaming slurry or the second foaming slurry.

According to the present disclosure, there can be provided a degradable artificial bone particle having a core-shell structure and a method for producing the same, which can satisfy the requirements for ceramic osteogenic properties, vascular properties and degradability.

Drawings

The disclosure will now be explained in further detail by way of example only with reference to the accompanying drawings, in which:

fig. 1 is a scene schematic diagram illustrating a degradable artificial bone particle according to an example of the present disclosure.

Fig. 2a is a schematic diagram illustrating the spherical morphology of a degradable artificial bone particle according to an example of the present disclosure.

Fig. 2b is a schematic diagram illustrating the surface topography of a degradable artificial bone particle according to an example of the present disclosure.

Fig. 2c is a schematic diagram illustrating a through-hole of a degradable artificial bone particle according to an example of the present disclosure.

Fig. 2d is a schematic diagram illustrating the internal topography of a degradable artificial bone particle according to an example of the present disclosure.

Fig. 3 is a schematic diagram illustrating the structure of a degradable artificial bone particle according to an example of the present disclosure.

Fig. 4 is a flow chart illustrating a method for preparing degradable artificial bone particles according to an example of the present disclosure.

Fig. 5 is a waveform diagram illustrating different extrusion rates in a method of preparing a degradable artificial bone particle according to an example of the present disclosure.

Fig. 6 is an osteogenic schematic diagram illustrating a degradable artificial bone granule according to examples of the present disclosure.

The main reference numbers illustrate:

1 … artificial bone material, 10 … artificial bone particles, D … artificial bone particles, D1 … first aperture, D2 … second aperture, 11 … inner core layer, 12 … outer shell layer, R1 … inner core layer radius, and R2 … outer shell layer outer diameter.

Detailed Description

Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. In the following description, the same components are denoted by the same reference numerals, and redundant description thereof is omitted. The drawings are schematic and the ratio of the dimensions of the components and the shapes of the components may be different from the actual ones.

It is noted that the terms "comprises," "comprising," and "having," and any variations thereof, in this disclosure, for example, a process, method, system, article, or apparatus that comprises or has a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include or have other steps or elements not expressly listed or inherent to such process, method, article, or apparatus. It will be understood by those within the art that, in general, terms used in the present disclosure are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

In addition, the headings and the like referred to in the following description of the present disclosure are not intended to limit the content or scope of the present disclosure, but merely serve as a reminder for reading. Such a subtitle should neither be understood as a content for segmenting an article, nor should the content under the subtitle be limited to only the scope of the subtitle.

The present disclosure relates to a degradable artificial bone particle 10 having a core-shell structure and a method for preparing the same, which can satisfy the requirements of ceramic osteogenesis, vascular formation and degradation properties according to the present disclosure. The degradable artificial bone particle 10 may be simply referred to as an artificial bone particle 10.

Fig. 1 is a scene schematic diagram illustrating a degradable artificial bone particle 10 according to an example of the present disclosure. Fig. 2a is a schematic diagram illustrating the spherical morphology of a degradable artificial bone particle 10 according to an example of the present disclosure. Fig. 2b is a schematic diagram illustrating the surface topography of a degradable artificial bone particle 10 according to an example of the present disclosure. Fig. 2c is a schematic diagram illustrating a through-hole of the degradable artificial bone particle 10 according to an example of the present disclosure. Fig. 2d is a schematic diagram illustrating the internal topography of a degradable artificial bone particle 10 according to an example of the present disclosure. Fig. 3 is a schematic diagram illustrating the structure of a degradable artificial bone particle 10 according to an example of the present disclosure.

In the present disclosure, a plurality of degradable artificial bone particles 10 are stacked on each other at a bone defect of a host bone 2 to form an artificial bone material 1 (see fig. 1). The artificial bone material 1 formed by the artificial bone particles 10 can be used for repairing and filling bone defects after benign bone tumor resection, vertebral body fusion and the like, can also be used for repairing bone defects with small openings and large inner cavities or minimally invasive operations, such as bone grafting filling in plastic surgery and stomatology, can also be used for repairing bone defects after spinal intervertebral bone grafting fusion and scraping of bone nuclear focuses, femoral head necrosis collapse repair, repairing bone defects after benign bone tumor resection, or in minimally invasive operations, such as alveolar ridge expansion, filling and repairing bone defects around periodontium and implants, and the like.

In some examples, the artificial bone material 1 formed by stacking the artificial bone particles 10 may have a three-dimensional porous structure. The porosity of the artificial bone material 1 may be 65% to 80%, in which case the artificial bone material 1 simulates natural bone tissue, facilitating the adhesion, growth and creeping of osteoblasts on the surface of the artificial bone particles 10 of the artificial bone material 1, and satisfying the conditions for regeneration and repair of bone tissue. Meanwhile, the mutually communicated (namely three-dimensional communicated) knots among the pores can ensure the transmission of nutrient substances and metabolic waste. In some examples, the porosity may be 65%, 70%, 75%, or 80%.

In some examples, the diameter of the macropores in the pores in the artificial aggregate 1 may be 100-800 μm. For example, the macropore diameter may be 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm or 800 μm. In this case, the distribution of the macropore diameters of the artificial aggregate 1 satisfies the condition for bone tissue regeneration and repair and facilitates the adhesion and spreading of osteoblasts.

In some examples, the degradable artificial bone particle 10 may be spherical in shape (see fig. 2a and 2 b). For example, the shape may be a regular sphere. In this case, the degradable artificial bone particles 10 having a regular spherical shape have good fluidity and can fill a bone defect site having an arbitrary three-dimensional shape.

In some examples, the diameter of the spherical degradable artificial bone particle 10 may be denoted by D (see fig. 2 b). The diameter D may be 0.5mm to 30 mm. Thereby, degradable artificial bone particles 10 of different diameters can be selected according to different application scenarios. In some examples, the diameter D of the degradable artificial bone particle 10 may be 0.5mm to 2 mm. For example, the diameter D of the degradable artificial bone particle 10 may be 0.5mm, 0.8mm, 1mm, 1.2mm, 1.5mm, 1.8mm, or 2 mm. The degradable artificial bone particles 10 with the diameter D of 0.5mm-2mm can be suitable for repairing the defects of oral cavity and maxillofacial bone. In some examples, the diameter D of the degradable artificial bone particle 10 may be 2mm to 30 mm. For example, the diameter D of the degradable artificial bone particle 10 may be 2mm, 5mm, 8mm, 10mm, 12mm, 15mm, 18mm, 20mm, 22mm, 25mm, 28mm, or 30 mm. The degradable artificial bone particle 10 with the diameter D of 2mm-30mm can be suitable for repairing the spine and the trunk bone.

In some examples, the degradable artificial bone particle 10 may be a calcium phosphate based bioactive ceramic. The degradable artificial bone particle 10 may have a core-shell structure. Namely, the degradable artificial bone particles 10 with the core-shell structure can be calcium phosphate-based bioactive ceramics. In this case, the degradable artificial bone particles 10 can be biodegraded at the bone defect and gradually replaced by new bone tissue after being implanted into the bone defect of the host bone 2.

In some examples, the core-shell structure may include an inner core layer 11. The inner core layer 11 may be in a ceramic phase. In other words, the inner core layer 11 may be formed of a calcium phosphate-based bioactive ceramic. Specifically, the inner core layer 11 may be selected from at least one of Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), and Biphasic Calcium Phosphate (BCP). Thus, the inner core layer 11 is biodegradable.

In some examples, the core-shell structure may include an outer shell layer. The outer shell layer may be wrapped around the outer surface of the inner core layer 11.

In some examples, the outer shell layer 12 may be in a ceramic phase. In other words, the outer shell layer 12 may be formed of a calcium phosphate-based bioactive ceramic. Specifically, the outer shell layer 12 may be selected from at least one of Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), Biphasic Calcium Phosphate (BCP). Thus, the outer shell layer 12 is biodegradable.

In some examples, the material of the inner core layer 11 may be different from the material of the outer shell layer 12. In this case, the inner core layer 11 and the outer shell layer 12 having different ceramic osteogenic, angiogenetic and degradability properties can be obtained.

In some examples, the degradation rate of the inner core layer 11 may be less than the degradation rate of the outer shell layer 12. In this case, the degradable artificial bone particle 10 having a core-shell structure with a corresponding degradation rate is obtained on demand.

In some examples, the core layer 11 may be HA and the outer shell layer 12 may be β -TCP. The beta-TCP is an outer shell layer, the HA is an inner core layer, the outer shell layer of the degradable artificial bone particles HAs strong angiogenesis capacity, and the inner core layer is slowly degraded and provides mechanical support. Is suitable for repairing the parts needing to be remolded and blood-moving, such as femoral head necrosis filling and the like.

In some examples, the core layer 11 may be HA and the outer shell layer 12 may be BCP. The outer shell layer of the degradable artificial bone particles with HA as an inner core layer and BCP as an outer shell layer HAs proper osteogenesis degrading capability, and the inner core layer is slowly degraded to provide mechanical support. The new bone growth direction is from the outer shell layer to the inner core layer. Is suitable for repairing abundant non-bearing parts of bone trabecula.

In some examples, the core layer 11 may be a BCP and the outer shell layer 12 may be a β -TCP. The outer shell layer of the degradable artificial bone particles with BCP as an inner core layer and beta-TCP as an outer shell layer has higher angiogenesis promoting activity. The degradation rate of the inner core layer is less than the degradation rate of the outer shell layer, and the degradation rate of the inner core layer is matched with the new bone formation rate. The bone conduction capability of the inner core layer is superior to that of the outer shell layer.

In some examples, the ratio of the radius R1 (see fig. 3) of the inner core layer 11 to the outer diameter R2 of the outer shell layer 12 may be 1:2 to 1: 3. For example, R1: r2 ═ 1: 2.5. the inner diameter of the outer shell layer 12 is equal to the radius R1 of the inner core layer 11.

In some examples, the inner core layer 11 and the outer shell layer 12 may be porous structures.

In some examples, the porous structure may include a plurality of through-holes having a first pore size. The first aperture may be denoted d1 (see fig. 2 c).

In some examples, the respective holes of the plurality of through holes may be interconnected.

In some examples, the first aperture d1 may be 30 μm-400 μm. In this case, osteoblasts can enter the artificial bone particles 10 through the through-holes, and adhesion, spreading, crawling, and proliferation of osteoblasts on the artificial bone particles 10 are facilitated. In some examples, for example, the first aperture d1 may be 30 μm, 50 μm, 80 μm, 100 μm, 120 μm, 150 μm, 180 μm, 200 μm, 220 μm, 250 μm, 280 μm, 300 μm, 320 μm, 350 μm, 380 μm, or 400 μm.

In some examples, the porous structure may include a plurality of micropores having a second pore size. The second aperture may be denoted as d2 (see fig. 2 d).

In some examples, the second aperture d2 may be 0.1 μm to 2 μm. In this case, it is possible to facilitate adhesion, spreading, crawling and proliferation of osteoblasts on the artificial bone particles 10. In some examples, for example, the second pore size d2 may be 0.1 μm, 0.3 μm, 0.5 μm, 0.8 μm, 1 μm, 1.2 μm, 1.5 μm, 1.8 μm, or 2 μm.

In some examples, the first aperture d1 may be larger than the second aperture d 2.

In the present disclosure, the degradable artificial bone particle 10 having a core-shell structure may include an inner core layer 11 and an outer shell layer 12 coated on an outer surface of the inner core layer 11. The inner core layer 11 may be of a different material than the outer shell layer 12. The inner core layer 11 and the outer shell layer 12 may be in a ceramic phase. The degradation rate of the inner core layer 11 may be less than the degradation rate of the outer shell layer 12. The outer shell layer 12 may be a porous structure. The porous structure may include a plurality of through-holes having a first pore size d1 and a plurality of micro-pores having a second pore size d 2. The holes of the plurality of through holes may be communicated with each other. The inner core layer 11 may be selected from at least one of hydroxyapatite, β -tricalcium phosphate, biphasic calcium phosphate. The outer shell layer 12 may be selected from at least one of hydroxyapatite, beta tricalcium phosphate, biphasic calcium phosphate. In this case, the artificial bone particle 10 having a good balance among ceramic osteogenic property, vascularization property and degradation property can be obtained based on actual needs.

The degradable artificial bone particles to which the present disclosure relates are not limited thereto, and in some examples, the core-shell structure may further include a single-layer wrapping layer (not shown). The single-layer wrapping layer may be disposed on an outer surface of the outer shell layer. In this case, a degradable artificial bone particle having a three-layer structure can be obtained. The degradable artificial bone particle with the three-layer structure has better ceramic osteogenesis, vascular formation and degradation performance.

In some examples, the single layer wrapping may be in a ceramic phase. In other words, the single-layer wrapping layer may be formed of a calcium phosphate-based bioactive ceramic. Specifically, the single-layer coating layer may be selected from at least one of Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), and Biphasic Calcium Phosphate (BCP). Thus, the single-layer wrapping is biodegradable.

In some examples, the material of the outer shell layer may be different from the material of the single wrap layer. In this case, the degradation rate of the outer shell is different from the degradation rate of the single wrap.

In some examples, the single wrap layer may be a porous structure. The description of the porous structure may be analogous to that of the inner core layer 11 or the outer shell layer 12.

In other examples, the core-shell structure may further include a multi-layer wrapping (not shown). A multi-layer wrap may be provided on the outer surface of the outer shell layer 12. That is, the plurality of wrapping layers are sequentially wrapped on the outer surface of the outer shell layer 12 along the radial direction. In this case, a degradable artificial bone particle having a multilayered structure can be obtained. The degradable artificial bone particles with the multilayer structure have good ceramic osteogenic property, vascular property and degradation property.

In some examples, each of the plurality of wraps may be in a ceramic phase. In other words, each of the wrapping layers may be formed of a calcium phosphate-based bioactive ceramic. Specifically, each of the coating layers may be selected from at least one of Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), Biphasic Calcium Phosphate (BCP). Thus, the single-layer wrapping is biodegradable.

In some examples, the material of the outer shell layer 12 is different from the material of the wrapping layer disposed directly on the outer surface of the outer shell layer 12. In this case, the degradation rate of the outer shell layer is different from that of the wrapping layer directly disposed on the outer surface of the outer shell layer.

In some examples, the material of the plurality of wraps is different between adjacent wraps. In this case, the degradation rate differs between adjacent wraps in the multi-layer wrap.

The present disclosure also relates to a method of preparing the degradable artificial bone particle 10. The degradable artificial bone particle 10 can be obtained by the following method for preparing a degradable artificial bone particle. The preparation method of the artificial bone particle related to the present disclosure can obtain the degradable artificial bone particle 10 which meets the requirements of ceramic osteogenesis, vascular formation and degradation performance. The following detailed description is made with reference to the accompanying drawings.

Fig. 4 is a flow chart illustrating a method for preparing degradable artificial bone particles according to an example of the present disclosure. Fig. 5 is a waveform diagram illustrating different extrusion rates in a method of preparing a degradable artificial bone particle according to an example of the present disclosure.

In some examples, as shown in fig. 4, the method for preparing the degradable artificial bone particle may include obtaining a first foaming slurry and a second foaming slurry (step S100), obtaining a ceramic green body based on the first foaming slurry and the second foaming slurry (step S200), and obtaining the artificial bone particle 10 based on the ceramic green body (step S300).

In some examples, obtaining a first foamed slurry in step S100 may include preparing a first calcium phosphate powder, an alginate solution, a binder.

In some examples, the first calcium phosphate powder in step S100 may have biological activity. The first calcium phosphate powder may be at least one selected from Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), and Biphasic Calcium Phosphate (BCP).

In step S100, the first calcium phosphate powder may be pretreated. Pretreatment may include mixing, stirring, washing, and centrifugation.

Specifically, the pre-treatment may include mixing the first calcium phosphate powder with deionized water and stirring thoroughly with a stirrer. The stirrer may be, but is not limited to, a glass rod.

The pretreatment can include moving the stirred mixture of the first calcium phosphate powder and the deionized water into a cleaner for shaking, and then transferring the mixture into a centrifuge for centrifugation at a rotating speed of 3000r/min-3200 r/min. Centrifuging and removing supernatant to obtain the pretreated first calcium phosphate powder. In this case, impurities of the first calcium phosphate powder can be removed by mixing, stirring, washing and centrifuging to obtain a pure first calcium phosphate powder.

In some examples, the oscillation time may be 5-10 min. For example, the shaking time may be 5min, 6min, 7min, 8min, 9min, or 10 min. In some examples, sonication within the ultrasonic cleaner may be utilized. In some examples, the rotational speed of the centrifuge may be 3000r/min, 3100r/min, or 3200 r/min. In some examples, the centrifugation time may be 3-5 min. For example, the shaking time may be 3min, 4min or 5 min.

In step S100, obtaining a first foaming slurry may include mixing a first calcium phosphate powder, an alginate solution, and a binder. For example, the first calcium phosphate powder may be a pretreated first calcium phosphate powder. The alginate solution may be a sodium alginate solution. The binder may be methylcellulose. In some examples, for example, a first calcium phosphate powder, a sodium alginate solution, and methylcellulose may be mixed. In some examples, the first calcium phosphate powder, sodium alginate solution, and binder may be homogeneously mixed while mixing is performed. The uniform mixing may be achieved by an emulsifying homogenizer.

In some examples, the methyl cellulose may be replaced with other binders. The other binder may be one of polyvinyl alcohol solution, polyethylene glycol solution, gelatin solution, and triethanolamine solution.

In step S100, obtaining a first foaming slurry may include adding a foaming agent and water to the mixed first calcium phosphate powder, alginate solution and binder, and stirring to obtain a first slurry. In some examples, the added water may be deionized water.

In step S100, obtaining the first foamed slurry may include heating the first slurry to obtain the first foamed slurry. In some examples, the heating process may be accomplished using a microwave oven. The power of the microwave oven can be 500-900W.

In some examples, the heating of the first slurry may be accomplished by multiple heating regimes. The number of heating times may be 3-6. For example, the number of heating times may be 4. The duration of each heating may be 6-15 s. For example, each heating period may be 8s, 10s or 12 s.

In some examples, obtaining the second foamed slurry in step S100 may include preparing a second calcium phosphate powder, an alginate solution, a binder.

In some examples, the second calcium phosphate powder in step S100 may have biological activity. The second calcium phosphate powder may be at least one selected from Hydroxyapatite (HA), β -tricalcium phosphate (β -TCP), and Biphasic Calcium Phosphate (BCP).

In some examples, the second calcium phosphate powder may be pre-treated. The pretreatment of the second calcium phosphate powder may be performed as described above with reference to the pretreatment of the first calcium phosphate powder. In this case, impurities in the second calcium phosphate powder can be removed, and the second calcium phosphate powder can be obtained in a pure state.

In some examples, the second calcium phosphate powder in step S100 is different from the first calcium phosphate powder. In some examples, the degradation rate of the first calcium phosphate powder can be less than the degradation rate of the second calcium phosphate powder. In some examples, for example, the first calcium phosphate powder is HA and the second calcium phosphate powder is β -TCP. In some examples, the first calcium phosphate powder is HA and the second calcium phosphate powder is BCP. In some examples, for example, the first calcium phosphate powder is BCP and the second calcium phosphate powder is β -TCP. Examples of the present disclosure are not limited thereto, and in some examples, the degradation rate of the first calcium phosphate powder may be greater than the degradation rate of the second calcium phosphate powder.

In step S100, obtaining a second foamed slurry may include mixing a second calcium phosphate powder, an alginate solution, and a binder. For example, a second calcium phosphate powder, sodium alginate solution, and methylcellulose may be mixed. Reference may be made in particular to the above description of the mixing process for obtaining the first foamed slurry.

In step S100, obtaining a second foaming slurry may include adding a foaming agent and water to the mixed second calcium phosphate powder, alginate solution and binder, and stirring to obtain a second slurry. Reference may be made in particular to the above description of the stirring process for obtaining the first slurry.

In step S100, obtaining a second foamed slurry may include heating the second slurry to obtain the second foamed slurry. In some examples, the heating process may be accomplished using a microwave oven. Reference may be made in particular to the above description relating to the heat treatment to obtain the first slurry.

In some examples, the alginate solution in step S100 may be a sodium alginate solution. In this case, the degradable artificial bone particles having abundant micropores can be obtained using sodium alginate.

In some examples, the concentration of the alginate solution in step S100 is adjustable. In this case, through the adjustment to the concentration of alginate solution, can be based on the application scene be convenient for follow-up acquisition of the artifical bone particle of different diameters size.

In some examples, the binder in step S100 may bind the first calcium phosphate powder or the second calcium phosphate powder. In some examples, the binder may be methylcellulose. In this case, the first calcium phosphate powder or the second calcium phosphate powder can be bonded with methylcellulose.

In some examples, the foaming agent in step S100 may be a hydrogen peroxide solution. In this case, hydrogen peroxide (i.e., aqueous hydrogen peroxide) is decomposed by heating to generate bubbles to obtain the first foamed slurry or the second foamed slurry. Therefore, the hydrogen peroxide is decomposed to generate bubbles, so that the first foaming slurry and the second foaming slurry have through air holes.

In some examples, hydrogen peroxide (H) in hydrogen peroxide₂O₂) Uniformly dispersing in the first slurry or the second slurry, and heating the first slurry or the second slurry to obtain a slurry H₂O₂The bubbles are generated, and the generated bubbles form through pores, so that the formed first foamed slurry or second foamed slurry has a plurality of through pores. In this case, the through-pores can be formed as through-holes having a first pore diameter that can degrade the artificial bone particles in subsequent processes.

In some examples, the volume fraction of blowing agent may be 20% to 50%. For example, the volume fraction of the blowing agent may be 20%, 30%, 40%, 50%.

In some examples, the ratio of the calcium phosphate powder (first or second calcium phosphate powder) to the deionized water may be 1:5 to 1: 20. For example, the ratio of the first calcium phosphate powder to the deionized water may be 1:5, 1:7, 1:10, 1:12.5, 1:15, 1:17, 1: 20.

In some examples, the mass ratio of the calcium phosphate powder (first calcium phosphate powder or second calcium phosphate powder) to the alginate powder can be 6: 1 to 10: 1. For example, the mass ratio of calcium phosphate powder to alginate powder may be 6: 1, 7: 1, 8: 1, 9: 1 or 10: 1.

In some examples, the volume ratio of alginate solution to binder may be from 5: 1 to 10: 1. For example, the volume ratio of alginate solution to binder may be 5: 1, 6: 1, 7: 1, 8: 1, 9: 1 or 10: 1.

In some examples, the mass fraction of alginate solution may be 4 wt% to 6 wt%. For example, the mass fraction of alginate solution may be 4 wt%, 5 wt% or 6 wt%.

In some examples, the mass fraction of the binder may be 2 wt% to 3 wt%. For example, the mass fraction of binder may be 2 wt%, 2.5 wt% or 3 wt%.

In some examples, the volume ratio of deionized water to blowing agent added to make the first slurry or the second slurry may be from 10: 1 to 20: 1. For example, the volume ratio of deionized water to blowing agent can be 10: 1, 12: 1, 14: 1, 16: 1, 18: 1, or 20: 1. In some examples, agitation may be performed with a high speed agitator until the blowing agent is uniformly dispersed.

In some examples, the deionized water may evaporate during heating using a microwave oven, and the deionized water may be continuously added during heating to ensure a volume ratio of deionized water to the blowing agent.

In some examples, the mass ratio of the foaming agent to the calcium phosphate powder (the first calcium phosphate powder or the second calcium phosphate powder) may be 1:2 to 1: 2.5.

In some examples, obtaining the ceramic green body based on the first and second foaming slurries in step S200 may include extruding the first and second foaming slurries to form a mixed sphere in which the second foaming slurry wraps the first foaming slurry. This makes it possible to obtain a liquid hybrid sphere having a core-shell structure. In other words, the mixed spheroids are core-shell structured droplets.

In step S200, the extrusion rate of the first foamed paste and the extrusion rate of the second foamed paste are respectively varied in the form of a sine wave during the extrusion molding. In this case, the mixed spheroids can be obtained automatically and continuously.

In some examples, the first foamable slurry and the second foamable material may be separately extruded using a coaxial two-layer nozzle in extrusion molding. In particular, the coaxial two-layer showerhead may include a core layer channel and a shell layer channel. Wherein the core layer channel may be used to extrude the first foamed slurry. The sheath channels may be used to extrude the second foamed material. In the extrusion molding, the first foamed slurry passing through the core layer passage and the second foamed material passing through the shell layer passage are simultaneously output. The coaxial double-layer spray head can be short for a coaxial double-spray head micro-fluidic system.

In some examples, the coaxial double layer spray head may be a coaxial double layer needle. Examples of the disclosure are not limited thereto.

In some examples, the ratio of the extrusion rate of the first foamed slurry to the extrusion rate of the second foamed material is from 1:3 to 1: 4. In this case, the extrusion rates of the first and second foaming pastes can be matched to automatically and continuously produce mixed spheroids of core-shell structure. In some examples, the extrusion rate of the first foamed slurry or the extrusion rate of the second foamed material may be achieved by software control. In some examples, the flow rate of the first foamable slurry and the flow rate of the second foamable material may be 2 to 20mL/min, respectively.

In some examples, the phase difference of the sine wave of the extrusion rate of the second foamed slurry and the sine wave of the extrusion rate of the first foamed slurry may be 45 degrees to 90 degrees. In this case, the extrusion rates of the first and second foaming pastes can be matched to automatically and continuously produce mixed spheroids of core-shell structure. For example, the phase of the sine wave of the extrusion rate of the second foamed slurry may be delayed by 45 degrees to 90 degrees from the phase of the sine wave of the extrusion rate of the first foamed slurry. For example, 45 degrees, 60 degrees, 90 degrees may be used.

In some examples, the extrusion rate of the first foamed slurry may be referred to as a flow rate of the first foamed slurry. The extrusion rate of the second foamed slurry may be referred to as a flow rate of the second foamed slurry. For example, as shown in fig. 5, curve a represents the flow rate of the first foamed slurry. Curve B represents the flow rate of the second foamed slurry. The ratio of the flow rate of the first foamed slurry to the flow rate of the second foamed material may be 1: 3. the phase of the sine wave of the extrusion rate of the second foaming slurry may be delayed by 45 degrees from the phase of the sine wave of the extrusion rate of the first foaming slurry.

In some examples, the diameter of the coaxial dual layer showerhead is adjustable. Under the condition, the diameter of the coaxial double-layer nozzle can be adjusted, so that the artificial bone particles with different diameters can be conveniently obtained based on the application scene.

In some examples, obtaining the ceramic green body based on the first and second foaming slurries in step S200 may include curing the mixed spheroid to form the ceramic green body.

In some examples, the mixed spheroids may be added to a calcium chloride solution, such that calcium chloride in the calcium chloride solution and alginate in the mixed spheroids are cross-linked to form ceramic green bodies. In this case, the mixed spheroids can be cured to form a core-shell structured ceramic green body. But examples of the present disclosure are not limited thereto and the calcium chloride solution may be replaced with other soluble calcium salts, such as a calcium nitrate solution.

In some examples, the addition of the mixed spheroids to the calcium chloride solution may be achieved by gravity. In other words, the mixed spheroids are dropped into the calcium chloride solution under the action of gravity. In some examples, the mass fraction of the calcium chloride solution may be 5 wt% to 6 wt%. For example, the mass fraction of the calcium chloride solution may be 5 wt%, 5.5 wt%, or 6 wt%.

In some examples, as described above, the first and second foaming slurries may have through pores, and thus, the ceramic green bodies obtained based on the first and second foaming slurries may be porous gel microspheres.

In some examples, the ceramic green body may be washed and dried before firing. Specifically, the ceramic green body in the calcium chloride solution is taken out, and then washed and dried. Thereby facilitating the subsequent firing process. In some examples, the ceramic green body is taken out after being soaked in calcium chloride solution for 10-12h, washed with deionized water for 3-5 times, and then dried in a forced air drying oven at a temperature of 50-70 ℃. For example, the temperature condition of the forced air drying oven may be 60 ℃.

In some examples, obtaining the artificial bone particle 10 based on the ceramic green body in step S300 may include sintering the ceramic green body to obtain the artificial bone particle 10. Wherein, the sintering treatment can be realized by a muffle furnace.

In some examples, in the sintering process, the temperature is raised to 1100 ℃ at a heating rate of 3 ℃/min to 5 ℃/min, and the high-temperature sintering is carried out at the temperature of 1100 ℃ for 2 hours, and then the temperature is naturally reduced to the room temperature. In this case, the alginate can be decomposed and separated by a specific sintering process so that abundant micropores are left inside the artificial bone particles. The room temperature may be 25 to 30 ℃ and may be, for example, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ or 30 ℃. The rate of temperature rise may be, for example, 3 deg.C/min, 4 deg.C/min, or 5 deg.C/min.

In some examples, the artificial bone particle 10 may be spherical. The size of the artificial bone particle 10 may be represented by the diameter of the artificial bone particle 10. As described above, artificial bone particles 10 of different sizes can be obtained by adjusting the concentration of the alginate solution and the diameter of the coaxial double-layered nozzle. In this case, the artificial bone particles 10 of different diameter sizes can be obtained based on the application scene.

In the present disclosure, a first slurry is obtained using a first calcium phosphate powder, an alginate solution, a binder, a foaming agent, and water, the first slurry is heated to obtain a first foamed slurry, a second slurry is obtained using a second calcium phosphate powder, an alginate solution, a binder, a foaming agent, and water, the second slurry is heated to obtain a second foamed slurry, the first calcium phosphate powder and the second calcium phosphate powder are respectively selected from at least one of hydroxyapatite, β -tricalcium phosphate, and biphasic calcium phosphate, and the second calcium phosphate powder is different from the first calcium phosphate powder. In this case, the first and second foaming pastes have through pores by generating bubbles through decomposition of the foaming agent by heating. Extruding and molding the first foaming slurry and the second foaming slurry to form a mixed spheroid of the second foaming slurry and the first foaming slurry, and curing to form a ceramic blank, wherein in the extrusion molding process, the extrusion rate of the first foaming slurry and the extrusion rate of the second foaming slurry are respectively changed in a sine wave form; in this case, the mixed spheroids can be automatically and continuously obtained to form the ceramic green body of the core-shell structure. And sintering the ceramic blank to obtain the artificial bone particles. In this case, the ceramic green body is sintered to obtain artificial bone particles, and in this case, alginate is decomposed and detached during the sintering process to leave abundant micropores inside the artificial bone particles. In addition, the preparation method disclosed by the invention is simple to operate, quick to process and low in cost.

The preparation method of the present disclosure is not limited thereto, and in some examples, the artificial bone particles of the three-layer and above core-shell structure may be prepared using the preparation method of the present disclosure. Such as the above-mentioned three-layer structure artificial bone particles comprising a single-layer wrapping layer (hereinafter referred to as three-layer artificial bone particles) or multi-layer structure artificial bone particles comprising a multi-layer wrapping layer (hereinafter referred to as multi-layer artificial bone particles).

In some examples, the method for preparing the three-layered artificial bone particle may refer to the above-described steps of the two-layered structure of the artificial bone particle. The difference is that a third foaming slurry is needed when three layers of artificial bone particles are prepared. The third foamed slurry can be obtained by referring to the method for obtaining the first foamed slurry. In some examples, the third calcium phosphate powder of the third foaming slurry is different from the second calcium phosphate powder of the second foaming slurry. In some examples, the ceramic green body is obtained using the first foaming slurry, the second foaming slurry, and the third foaming slurry. The coaxial multi-layer spray head comprises a nuclear layer channel, a shell layer channel and a wrapping layer. The diameter of the wrapping may be greater than the shell passage. The wrapping layer may be used to output the third foamed slurry.

In some examples, the preparation method of the multilayered artificial bone particle may refer to the above-described steps of the bilayer-structured artificial bone particle. The difference is that when preparing the multilayer artificial bone particles, a plurality of foaming slurry parts except the first foaming slurry and the second foaming slurry are required to be obtained in the preparation method. The obtaining of each foamed slurry of the plurality of foamed slurries may be specifically referred to the obtaining method of the first foamed slurry. In some examples, the ceramic green body is obtained using the first foamed slurry, the second foamed slurry, and the multiple foamed slurries. The coaxial multilayer spray head comprises a nuclear layer channel, a shell layer channel and a multilayer wrapping layer channel. Each of the multi-wrap channels may have a diameter greater than the shell channel. Each of the plurality of wrapping layer channels is arranged at the periphery of the shell layer channel along the radial direction. Each wrap channel may be used to output a respective foamed slurry. In some examples, the sheath channel adjacent to the sheath channel outputs a foamed slurry having a calcium phosphate powder that is different from a second calcium phosphate powder of a second foamed slurry.

[ example 1 ]

In example 1, degradable artificial bone granules having a BCP outer shell layer and an HA inner core layer were prepared.

In example 1, 4g of bcp powder and 4g of ha powder were weighed and poured into two 250mL glass beakers, respectively, and 50mL of deionized water was added thereto, followed by sufficient stirring with a glass rod. And transferring the uniformly stirred slurry into a numerical control ultrasonic cleaner for ultrasonic oscillation for 10min, transferring the slurry into a 50mL centrifuge tube, and centrifuging for 3min at the rotating speed of 3000r/min in a low-speed centrifuge.

In example 1, the supernatant in the centrifuge tube was removed, and the ceramic precipitate was placed in a 250mL beaker, followed by adding 10mL of sodium alginate (Na Alg) having a mass fraction of 6 wt% and 2mL of Methylcellulose (MC) having a mass fraction of 2 wt% in this order, and mixing them uniformly with an emulsion homogenizer. Then adding 1.5mL of H with the volume fraction of 30 percent₂O₂And 20mL of deionized water, stirred well with a high speed stirrer until H₂O₂Dispersing uniformly to obtain two calcium phosphate slurries respectively containing HA and BCP components.

In example 1, microwave-assisted hydrogen peroxide foaming technology is adopted, andthe uniformly mixed calcium phosphate slurry was heated in a microwave oven 4 times for 10 seconds each. Make H in calcium phosphate slurry₂O₂The decomposition produces bubbles. When H is present₂O₂After complete decomposition, the slurry is stirred by a high-speed stirrer until the bubbles are moderate in size and uniform in distribution, and two foaming slurries of BCP and HA are obtained.

In example 1, BCP foaming slurry was extruded from the sheath channel of a coaxial double-walled needle. The HA foaming slurry was extruded from the core layer channel of a coaxial double-layer needle. Controlled by MICROLAB software, the extrusion rate of the foaming slurry in the core layer channel is 5mL/min, and the extrusion rate of the foaming slurry in the shell layer channel is 15 mL/min. The extrusion speed wave phase of the foaming slurry in the shell layer channel is shifted by 90 degrees backwards than that of the foaming slurry in the core layer channel. And forming a liquid drop with a core-shell structure on the needle head. Then dripping into 6 wt% calcium chloride solution (CaCl) under the action of gravity₂) In the method, gel microspheres with core-shell structures are gradually hardened through the crosslinking action of sodium alginate and calcium ions.

In example 1, the gel microspheres were taken out after 12h of immersion in calcium chloride solution, washed 5 times with deionized water, and dried in a forced air drying oven at 60 ℃ to obtain ceramic green bodies. Then sintering the mixture in a muffle furnace at a high temperature of 1100 ℃ for 2h at a heating rate of 5 ℃/min, and finally naturally cooling the mixture to room temperature of 25 ℃ to prepare the degradable artificial bone particles with the core-shell structure.

In example 1, the outer shell layer of the degradable artificial bone particles with HA as the inner core layer and BCP as the outer shell layer HAs proper bone degradation capability, and the inner core layer is slowly degraded to provide mechanical support. The new bone growth direction is from the outer shell layer to the inner core layer. Is suitable for repairing abundant non-bearing parts of bone trabecula. The macroscopic morphology of the degradable artificial bone particles obtained in the embodiment 1 is spherical, and the sphericity is good.

[ example 2 ]

In example 2, degradable artificial bone granules having an outer shell layer of β -TCP and an inner core layer of HA were prepared. The preparation method is as in example 1. The preparation method in example 2 differs from the preparation method in example 1 in that: the powder selected in example 2 was 4gHA powder, 4g beta-TCP powder. In addition, in the presence of H₂O₂And deionized water 15mL when stirred well using a high speed stirrer. Extruding the beta-TCP foaming slurry from a shell layer channel of the coaxial double-layer needle head. The HA foaming slurry was extruded from the core layer channel of a coaxial double-layer needle.

In example 2, the outer shell layer of the degradable artificial bone particles, in which β -TCP is the outer shell layer and HA is the inner core layer, HAs a strong angiogenesis ability, and the inner core layer is slowly degraded to provide mechanical support. Is suitable for repairing the parts needing to be remolded and blood-moving, such as femoral head necrosis filling and the like.

[ example 3 ]

In example 3, degradable artificial bone granules having an HA outer shell layer and a BCP inner core layer were prepared. The preparation method is as in example 1. The preparation method in example 3 differs from the preparation method in example 1 in that: and extruding HA foaming slurry from a shell channel of the coaxial double-layer needle head. Extruding BCP foaming slurry from the core layer channel of the coaxial double-layer needle.

In example 3, HA provides the shell mechanical support for the outer shell layer and BCP provides the outer shell layer of the degradable artificial bone particles of the inner core layer, and bone cells enter the inner core layer through the through holes to form bone. The new bone growth direction is from the inner nuclear layer to the outer shell layer. Is suitable for bone repair of a load-bearing part.

Fig. 6 is an osteogenic schematic diagram illustrating a degradable artificial bone granule according to examples of the present disclosure. Fig. 6a is a schematic diagram of osteogenesis of degradable artificial bone particles with HA as an inner core layer and BCP as an outer shell layer. Fig. 6b is a schematic diagram of osteogenesis of degradable artificial bone granules with HA as the outer shell layer and BCP as the inner core layer. Then, the artificial bone particles obtained in examples 1 to 3 and the artificial bone material formed from the artificial bone particles were characterized in the following manner:

(1) macro-morphology structure: directly observing the macro morphology of the prepared degradable artificial bone particles. The macro topography of example 1 is shown in fig. 2 a. The macro-topography of example 2 and example 3 was approximately the same as the macro-topography of example 1.

(2) Microstructure of the micro-morphology: when the degradable artificial bone particles are prepared, titanium metal elements are doped in slurry, and the core-shell structure is observed under X-ray. The core-shell structure of example 1 is shown in fig. 3. The titanium metal element is distributed in the shell layer, the brightness of the outer shell layer is high, and the brightness of the inner core layer is low. The core-shell structures of examples 2 and 3 are substantially the same as those of example 1.

In addition, the surface and cross section of the degradable artificial bone particles were observed by scanning electron microscopy at different magnifications. The corresponding magnifications of fig. 2b, 2c and 2d are 40 times, 50 times and 10000 times, respectively. The surface of example 1 is shown in fig. 2b and 2c, and the cross-section of example 1 is shown in fig. 2 d. The surface and cross section of examples 2 and 3 are substantially the same as those of example 1. The surface structure and the contour between the nucleocapsid layers of the artificial bone particles are complete, and the degradable artificial bone particles have a large number of through microporous structures.

(3) Bone formation effect test: the SD rat femoral condyle outside uses trephine to make the defect part of a cylinder with the diameter of 3mm and the height of 4mm, and uses forceps to take out the residual bone fragments in the hole, and degradable artificial bone particles are filled into the straight part of the defect part one by one until the filling is compact. The materials were taken 8 weeks after surgery, and the samples were subjected to decalcification, embedding, and the like, followed by soft tissue sectioning, and the results of H & E staining are shown in fig. 6a and 6 b. After the degradable artificial bone particle with HA as the inner core layer and BCP as the outer shell layer in example 1 shown in FIG. 6a is implanted, bone tissue grows inward from the periphery of the material. And as shown in fig. 6b, after the degradable artificial bone particles with HA as the outer shell layer and BCP as the inner core layer in example 3 are implanted, they gradually grow and aggregate inside to form large bone tissues. As the two types of artificial bone particles degrade, new bone tissue gradually replaces the material (i.e., the artificial bone particles). The osteogenesis method of example 2 was substantially the same as that of example 1.

In some instances, numbers expressing quantities of ingredients, properties such as concentrations, reaction conditions, and so forth, used to describe and claim certain examples of the present disclosure are to be understood as being modified in some instances by the term "about". Accordingly, in some examples, the numerical parameters set forth in the written description and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the particular example. In some examples, the numerical parameter should be interpreted in terms of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some examples of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. The numerical values presented in some examples of the disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

While the present disclosure has been described in detail in connection with the drawings and examples, it should be understood that the above description is not intended to limit the disclosure in any way. Those of skill in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present disclosure. Those skilled in the art can make modifications and variations to the present disclosure as needed without departing from the true spirit and scope of the disclosure, which fall within the scope of the disclosure.

Claims

1. A degradable artificial bone particle with a core-shell structure, which is characterized in that the degradable artificial bone particle has a core-shell structure, the core-shell structure comprises an inner core layer and an outer shell layer coated on the outer surface of the inner core layer, the material of the inner core layer is different from that of the outer shell layer, the inner core layer and the outer shell layer are in a ceramic phase, the degradation rate of the inner core layer is less than that of the outer shell layer, the inner core layer and the outer shell layer are in a porous structure, the porous structure comprises a plurality of through holes with a first pore size and a plurality of micropores with a second pore size, the pores of the through holes are communicated with each other, the inner core layer is selected from at least one of hydroxyapatite and biphasic calcium phosphate, the outer shell layer is selected from at least one of beta-tricalcium phosphate and biphasic calcium phosphate, and the first pore size is greater than the second pore size, the first aperture is 30-400 mu m, and the second aperture is 0.1-2 mu m.

2. The degradable artificial bone particle of claim 1, wherein:

the core-shell structure further comprises a single-layer wrapping layer arranged on the outer surface of the outer shell layer, the single-layer wrapping layer is selected from at least one of hydroxyapatite, beta-tricalcium phosphate and biphase calcium phosphate, and the material of the outer shell layer is different from that of the single-layer wrapping layer.

3. The degradable artificial bone particle of claim 1, wherein:

the core-shell structure further comprises a plurality of wrapping layers arranged on the outer surface of the outer shell layer, each wrapping layer in the plurality of wrapping layers is selected from one of hydroxyapatite, beta-tricalcium phosphate and biphase calcium phosphate, the material of the outer shell layer is different from that of the wrapping layer directly arranged on the outer surface of the outer shell layer, and the material of the adjacent wrapping layers in the plurality of wrapping layers is different.

4. The method for preparing the degradable artificial bone particle of claim 1, comprising: preparing and mixing first calcium phosphate powder, an alginate solution and a binder, adding a foaming agent and water, stirring to obtain first slurry, and heating the first slurry to obtain first foaming slurry, wherein the first calcium phosphate powder is selected from at least one of hydroxyapatite and biphasic calcium phosphate; preparing and mixing a second calcium phosphate powder, an alginate solution and a binder, adding a foaming agent and water, stirring to obtain a second slurry, and heating the second slurry to obtain a second foamed slurry, wherein the second calcium phosphate powder is selected from at least one of beta-tricalcium phosphate and biphasic calcium phosphate, and is different from the first calcium phosphate powder; extruding and molding the first foaming slurry and the second foaming slurry to form a mixed spheroid of the second foaming slurry and the first foaming slurry, and curing to form a ceramic blank, wherein in the extrusion molding process, the extrusion rate of the first foaming slurry and the extrusion rate of the second foaming slurry are respectively changed in a sine wave form; and sintering the ceramic green body to obtain the artificial bone particles.

5. The method of claim 4, wherein:

in the sintering treatment, the mixture is sintered at the high temperature of 1100 ℃ for 2 hours at the heating rate of 3-5 ℃/min, and then is naturally cooled to the room temperature.

6. The method of claim 4, wherein:

in the extrusion molding, a first foaming slurry and a second foaming material are respectively extruded by utilizing a coaxial double-layer nozzle, and the ratio of the extrusion rate of the first foaming slurry to the extrusion rate of the second foaming material is 1:3, the phase difference of the sine wave of the extrusion rate of the second foaming slurry to the sine wave of the extrusion rate of the first foaming slurry is 45-90 degrees.

7. The method of claim 6, wherein:

the size of the artificial bone particles is obtained by adjusting the concentration of the alginate solution and the diameter of the coaxial double-layer spray head.

8. The method of claim 4, wherein:

in the process of curing the mixed spheroids, adding the mixed spheroids into a calcium chloride solution, and crosslinking calcium chloride in the calcium chloride solution and alginate in the mixed spheroids to form a ceramic embryo.

9. The method of claim 4, wherein:

the alginate solution is sodium alginate solution, the binder is one of methylcellulose, polyvinyl alcohol solution, polyethylene glycol solution, gelatin solution and triethanolamine solution, and the foaming agent is hydrogen peroxide solution.